Immunologic memory plays a key role in protecting the host against reinfection with many pathogens, and memory T lymphocytes are of particular importance for protective immunity against viruses. Therefore, the induction of long-lived virus-specific memory T cells is a key objective of efforts to develop new or improved viral vaccines. However, the factors that control the evolution of the cellular immune response from the effector phase into long-term memory have not been fully defined, especially in humans. Our studies have characterized the T cell response to immunodominant epitopes of two live virus vaccines, vaccinia virus and yellow fever virus, as models for acute virus infections in man. Data from these studies challenge certain paradigms derived from studies in experimental mice. We propose to test the hypothesis that persistence of human virus-specific memory T cells depends upon their functional properties and their early expression of survival factors. The Specific Aims of the project are: 1. Define the relationship between the virus-specific T cell repertoires at serial time points from the acute through the memory phase of the T cell response using flow cytometry and molecular analysis of T cell receptor gene rearrangements. 2. Define the relationship between the expression of survival factors during the acute phase of the T cell response and T cell clonal persistence during long-term memory. 3. Define the relationship between functional profiles of virus-specific T cells and their persistence during long-term memory. This Project will contribute to the overall Program Project objectives through its focus on human T cell memory to non-persistent virus infections. It will interact with Projects 1 and 2 to develop techniques for analysis of rare antigen-specific T cell populations, and will utilize the services and expertise of the Tetramer, Flow Cytometry, TCR Analysis, and Administrative Cores. This research seeks to understand how the body's infection-fighting system develops after infection with viruses. This information will help to improve vaccines against virus infections.